Antiepileptic drugs in critically ill patients.

BACKGROUND: The incidence of seizures in intensive care units ranges from 3.3% to 34%. It is therefore often necessary to initiate or continue anticonvulsant drugs in this setting. When a new anticonvulsant is initiated, drug factors, such as onset of action and side effects, and patient factors, such as age, renal, and hepatic function, should be taken into account. It is important to note that the altered physiology of critically ill patients as well as pharmacological and nonpharmacological interventions such as renal replacement therapy, extracorporeal membrane oxygenation, and target temperature management may lead to therapeutic failure or toxicity. This may be even more challenging with the availability of newer antiepileptics where the evidence for their use in critically ill patients is limited. MAIN BODY: This article reviews the pharmacokinetics and pharmacodynamics of antiepileptics as well as application of these principles when dosing antiepileptics and monitoring serum levels in critically ill patients. The selection of the most appropriate anticonvulsant to treat seizure and status epileptics as well as the prophylactic use of these agents in this setting are also discussed. Drug-drug interactions and the effect of nonpharmacological interventions such as renal replacement therapy, plasma exchange, and extracorporeal membrane oxygenation on anticonvulsant removal are also included. CONCLUSION: Optimal management of antiepileptic drugs in the intensive care unit is challenging given altered physiology, polypharmacy, and nonpharmacological interventions, and requires a multidisciplinary approach where appropriate and timely assessment, diagnosis, treatment, and monitoring plans are in place.

Neurologic manifestations of intravascular large B-cell lymphoma.

PURPOSE OF REVIEW: Intravascular large B-cell lymphoma is a rare subtype of large B-cell lymphoma that affects various organs including the nervous system. The diagnosis is challenging and frequently made at autopsy. RECENT FINDINGS: We report 5 cases with an array of neurologic manifestations. All patients were initially evaluated for alternative diagnoses. Three patients were diagnosed at autopsy, one with brain biopsy, and another with muscle biopsy. Muscle was involved in all 3 patients who had muscle tissue available for analysis. SUMMARY: Our observations suggest that random open muscle biopsy may present a high-yield, less invasive option for the diagnosis of this disorder.

Modafinil attenuates reinstatement of cocaine seeking: role for cystine-glutamate exchange and metabotropic glutamate receptors.

Modafinil may be useful for treating stimulant abuse, but the mechanisms by which it acts to do so are unknown. Indeed, a primary effect of modafinil is to inhibit dopamine transport, which typically promotes rather than inhibits motivated behavior. Therefore, we examined the role of nucleus accumbens extracellular glutamate and the group II metabotropic glutamate receptor (mGluR2/3) in modafinil effects. One group of rats was trained to self-administer cocaine for 10 days and extinguished, then given priming injections of cocaine to elicit reinstatement. Modafinil (300 mg/kg, intraperitoneal) inhibited reinstated cocaine seeking (but did not alter extinction responding by itself), and this effect was prevented by pre-treatment with bilateral microinjections of the mGluR2/3 antagonist LY-341495 (LY) into nucleus accumbens core. No reversal of modafinil effects was seen after unilateral accumbens core LY, or bilateral LY in the rostral pole of accumbens. Next, we sought to explore effects of modafinil on extracellular glutamate levels in accumbens after chronic cocaine. Separate rats were administered non-contingent cocaine, and after 3 weeks of withdrawal underwent accumbens microdialysis. Modafinil increased extracellular accumbens glutamate in chronic cocaine, but not chronic saline-pre-treated animals. This increase was prevented by reverse dialysis of cystine-glutamate exchange or voltage-dependent calcium channel antagonists. Voltage-dependent sodium channel blockade partly attenuated the increase in glutamate, but mGluR1 blockade did not. We conclude that modafinil increases extracellular glutamate in nucleus accumbens from glial and neuronal sources in cocaine-exposed rats, which may be important for its mGluR2/3-mediated antirelapse properties.

Estrogen pretreatment modulates morphine-induced conditioned place preference in ovariectomized mice.

Estrogen is known to modulate the neurotransmission in the brain. The main aim of this study was to investigate the effects of estrogen on the rewarding properties of morphine using conditioned place preference (CPP) paradigm in adult female mice. The possible rewarding effect of estrogen was also examined in ovariectomized mice. Following a 6-day conditioning procedure, sham operated animals showed a significant preference towards the side previously paired with a range of morphine doses (2, 5 and 10--but not 20--mg/kg, SC). However, ovariectomized mice showed decreased CPP compared to gonadally intact mice with a right shift in their morphine dose-response curve. These effects were reversed by chronic daily administration of estradiol benzoate (EB; 20 microg/kg, SC). Furthermore, in ovariectomized mice, EB per se was able to induce CPP. In conclusion, our findings indicate that estradiol has a facilitating effect on morphine reward while its deficiency increases the threshold dose of morphine to induce CPP.

Intra-hippocampal inhibition of protein kinase AII attenuates morphine-induced conditioned place preference.

Morphine and other drugs of abuse modulate protein kinase A (PKA) signaling within the mesolimbic reward pathway. Using a balanced conditioned place preference (CPP) paradigm, we studied the possible involvement of protein kinase AII (PKA II) on the acquisition, expression and consolidation of morphine place conditioning in male Wistar rats. Subcutaneous administration of various doses of morphine sulfate (1-9 mg/kg) induced CPP in a dose-dependent manner. H-89, a selective PKA II inhibitor, was administered into CA1 region of the hippocampus at 1, 2.5 and 5 microM/rat. Using a 3-day schedule of conditioning, it was found that the H-89 did not produce a significant place preference or place aversion. H-89 (1, 2.5 and 5 microM/rat) significantly reduced the time spent by rats in the morphine compartment when given immediately after each conditioning session (consolidation), whereas it had no effect when administered before morphine during the conditioning phase (acquisition) or before testing for place preference in the absence of morphine (expression). It is concluded that the PKA II may play an active role in the consolidation of reward-related memory of morphine in CA1 region of the hippocampus.

Radiosurgery for glomus jugulare tumors: experience treating 16 patients in Iran.

OBJECT: Glomus jugulare tumors (GJT) have traditionally been treated by surgery or fractionated external-beam radiotherapy. The aim of this retrospective study was to determine the tumor control rate, clinical outcome, and short-term complications of stereotactic radiosurgery in subsets of patients who are poor candidates for these procedures, based on age, medical problems, tumor size, or prior treatment failure. METHODS: The Leksell Gamma Knife was used to treat 16 patients harboring symptomatic, residual, recurrent, or unresectable GJTs. The age of the patients ranged from 12 to 77 years (median 46.5 years). Gamma Knife surgery (GKS) was performed as primary treatment in five patients (31.3%). Microsurgery preceded radiosurgery in 10 patients (62.5%) and fractionated radiotherapy in three patients (18.8%). The median tumor volume was 9.8 cm3 (range 1.7-20.6 cm3). The median marginal dose applied to a mean isodose volume of 50% (range 37-70%) was 18 Gy (range 14-20 Gy). Neurological follow-up examinations revealed improved clinical status in 10 patients (62.5%), a stable neurological status in six (37.5%), and no complications. After radiosurgery, follow-up imaging was conducted in 14 patients; the median interval from GKS to the last follow up was 18.5 months (range 4-28 months). Tumor size had decreased in six patients (42.9%), and the volume remained unchanged in the remaining eight (57.1%). None of the tumors increased in volume during the observation period. CONCLUSIONS: According to the authors' experience, GKS represents a useful therapeutic option to control symptoms and may be safely conducted in patients with primary or recurrent GJTs with no death and no acute morbidity. Because of the tumor's naturally slow growth rate, however, long-term follow-up data are needed to establish a cure rate after radiosurgery.